Alzheimers disease (AD) is an age-related neurodegenerative disorder, which affected in 2006 26 6 million people. Forecasts predict that the prevalence will quadruple by 2050, by which time 1 in 85 persons worldwide will be living with the disease (Brookmeyer et al. (2007)). AD manifests itself as progressive cognitive deficits, such as memory loss and a decline in mental abilities.
Central in the pathogenesis of AD is the accumulation of beta-amyloid peptide (Abeta) in the brain. Abeta is a cleavage product of the amyloid precursor protein (APP) which is sequentially cleaved in the amyloidogenic pathway, first by β-secretase and then by γ-secretase. The resulting Abeta fragments are of variable size, whereas the 40 amino acid peptide (Abeta40) is the most abundant species and the 42 amino acid peptide, the so-called Abeta42, is believed to be the most harmful species. Abeta can accumulate in the extracellular space of the brain, where it aggregates in a multistep process to form neurotoxic oligomeres and finally gives rise together with other substances to amyloid plaques, which are a typical hallmark of the Alzheimer disease.
A promising clinical immunologic approach for the treatment of Alzheimer's disease is passive immunization, in which antibodies against Abeta are administered to the subject in order to remove Abeta from the brain. Three different mechanisms for Abeta clearance through anti-Abeta antibodies have been proposed, which are not mutually exclusive: (1) the catalytic conversion of fibrillar Abeta to less toxic forms (Bard et al. (2000); Bacskai et al. (2001); Frenkel et al. (2000)); (2) the opsonization of Abeta deposits, leading to microglial phagocytosis (Bard et al. (2000); Bacskai et al. (2002); Frenkel et al. (2000); and (3) the promotion of the efflux of Abeta from the brain to the circulation (DeMattos et al. (2001)), the so-called peripheral sink hypothesis.
Mohajera et al. (2004) and Gaugler et al. (2005) of the University of Zurich have generated mouse antibodies against Abeta and studied the bioactivity of monoclonal murine anti-Abeta antibodies in vivo.
However, murine antibodies often result in immunogenicity when administrated to human beings. The elicited anti-globulin response limits the clinical utility of murine antibodies (Miller et al. (1983); Schroff et al. (1985)).
Hence, there is a need for new, non-immunogenic and effective antibodies for the treatment and/or diagnosis of Abeta-related disorders, specifically of Alzheimer's disease.